The vast majority of medications and biologically active natural products contain carbon- carbon bonds. The synthesis of these, and related small molecules, is therefore reliant on carbon-carbon bond-forming reactions. It follows that innovative approaches to efficient C-C bond formations will broaden the diversity of small molecules easily accessible and accelerate the discovery of drugs. The overall objective of this application is to develop novel and practical methods for sp3-C-H bond functionalizations/C-C couplings with very weakly acidic C-H's (pKa's 32 to over 40). Two mechanistic-based strategies are pursued to achieve this objective. The first involves activation of arenes toward mild deprotonation by coordination to transition metal catalysts, and encompasses enantioselective variants. Among the products of these reactions are tiarylmethanes and diarylmethylamines. The second approach is based on deprotonative cross-coupling procedures (DCCP's) wherein sp3-C-H's with pKa's as high as 35 are deprotonated under catalytic conditions and coupled with aryl halides. To perform this challenging class of reactions, new catalysts have been identified with unprecedented reactivity. By study of the mechanism of these catalysts, fundamentally new guiding principles have been revealed that are of interest to the greater chemistry community. This catalysts will be applied to DCCP's of unactivated diarylmethanes, allylbenzenes, N,N-dialkylbenzylamines, sulfoxides, sulfonamides, and sulfones to generate novel arylated products. The proposed method development, and mechanistic insight, will provide a collection of practical tools that enable new and efficient bond constructions that are easily applied to the synthesis of medications. The two approaches to C-C bond-formation in this application are innovative because they represent a clear departure from known chemistry.